Roles of the Dynamic Tumor Immune Microenvironment in the Individualized Treatment of Advanced Clear Cell Renal Cell Carcinoma

Abstract

Immune checkpoint inhibitors (ICIs) are currently a first-line treatment option for clear cell renal cell carcinoma (ccRCC). However, recent clinical studies have shown that a large number of patients do not respond to ICIs. Moreover, only a few patients achieve a stable and durable response even with combination therapy based on ICIs. Available studies have concluded that the response to immunotherapy and targeted therapy in patients with ccRCC is affected by the tumor immune microenvironment (TIME), which can be manipulated by targeted therapy and tumor genomic characteristics. Therefore, an in-depth understanding of the dynamic nature of the TIME is important for improving the efficacy of immunotherapy or combination therapy in patients with advanced ccRCC. Here, we explore the possible mechanisms by which the TIME affects the efficacy of immunotherapy and targeted therapy, as well as the factors that drive dynamic changes in the TIME in ccRCC, including the immunomodulatory effect of targeted therapy and genomic changes. We also describe the progress on novel therapeutic modalities for advanced ccRCC based on the TIME. Overall, this review provides valuable information on the optimization of combination therapy and development of individualized therapy for advanced ccRCC.

Integrative Analysis of the Genomic and Immune Microenvironment Characteristics Associated With Clear Cell Renal Cell Carcinoma Progression: Implications for Prognosis and Immunotherapy

“…The immune microenvironment of ccRCC has received considerable attention as increasing evidence suggested that it plays a crucial role in anti-cancer immunity ( 71 ). Previous studies have shown that ccRCC were inflammatory tumors accompanied by high infiltration of exhausted CD8 + TILs and immunosuppressive cells ( 72 ). We found high infiltration levels of CD8 + TILs and Tregs in early ccRCC, and increasing PDCD1 and LAG-3 levels with ccRCC progression in both cohorts.…”

Identification and Verification of m7G Modification Patterns and Characterization of Tumor Microenvironment Infiltration via Multi-Omics Analysis in Clear Cell Renal Cell Carcinoma

“…As one of the most immunologically distinct tumor types, ccRCC exhibited the highest angiogenesis score and is frequently infiltrated with immune cells when compared with other epithelial cancer types ( 71 ). The extent of T-cell infiltration is remarkably high in ccRCC ( 72 ), which leads to marked inflammatory features. However, as the most abundant immune cells, CD8 + T cells display impaired anti-tumor effects, which indicates that the immune microenvironment for ccRCC is unique compared with other tumors ( 73 ).…”

Identification of EZH2 as Cancer Stem Cell Marker in Clear Cell Renal Cell Carcinoma and the Anti-Tumor Effect of Epigallocatechin-3-Gallate (EGCG)

“…Studies have shown that 25–30% of ccRCC patients already had distant metastases at the time of initial diagnosis [ 51 ]. So far, angiogenesis inhibition with tyrosine kinase inhibitors (TKIs) combined with the inhibition of immune checkpoint proteins such as PD-1/PDL-1 and CTLA-4 have revolutionized the treatment landscape of ccRCC patients with metastases [ 52 , 53 ]. However, the responses are limited to a subgroup of patients and only approximately 5 to 30% of patients will primarily progress [ 54 ].…”